Aurora-A Expression Is Independently Associated with Chromosomal Instability in Colorectal Cancer

Abstract

AURKA (the official symbol for Aurora-A, STK15, or BTAK) regulates the function of centrosomes, spindles, and kinetochores for proper mitotic progression. AURKA overexpression is observed in various cancers including colon cancer, and a link between AURKA and chromosomal instability (CIN) has been proposed. However, no study has comprehensively examined AURKA expression in relation to CIN or prognosis using a large number of tumors. Using 517 colorectal cancers in two prospective cohort studies, we detected AURKA overexpression (by immunohistochemistry) in 98 tumors (19%). We assessed other molecular events including loss of heterozygosity (LOH) in 2p, 5q, 17q, and 18q, the CpG island methylation phenotype (CIMP), and microsatellite instability (MSI). Prognostic significance of AURKA was evaluated by Cox regression and Kaplan-Meier method. In both univariate and multivariate logistic regressions, AURKA overexpression was significantly associated with CIN (defined as the presence of LOH in any of the chromosomal segments; multivariate odds ratio, 2.97; 95% confidence interval, 1.40-6.29; P = .0045). In multivariate analysis, AURKA was associated with cyclin D1 expression (P = .010) and inversely with PIK3CA mutation (P=.014), fatty acid synthase expression (P=.028), and family history of colorectal cancer (P = .050), but not with sex, age, body mass index, tumor location, stage, CIMP, MSI, KRAS, BRAF, BMI, LINE-1 hypomethylation, p53, p21, beta-catenin, or cyclooxygenase 2. AURKA was not significantly associated with clinical outcome or survival. In conclusion, AURKA overexpression is independently associated with CIN in colorectal cancer, supporting a potential role of Aurora kinase-A in colorectal carcinogenesis through genomic instability (rather than epigenomic instability).

AURKA promotes cell migration and invasion of head and neck squamous cell carcinoma through regulation of the AURKA/Akt/FAK signaling pathway

“…Aurora kinase A (AURKA) has been implicated in numerous types of cancer, including colonic, breast, liver, gastric, uterine, ovarian, non-small cell lung, pancreatic and esophageal cancer (5)(6)(7)(8)(9)(10). Furthermore, a correlation has been observed between the overexpression of AURKA mRNA and tumor progression and shortened survival in patients with HNSCC (11).…”

Tanshinone I induces human colorectal cancer cell apoptosis: The potential roles of Aurora A-p53 and survivin-mediated signaling pathways

“…Bischoff et al were the first to report overexpression of Aurora A mRNA in >50% of CRC tumors (15). It was later reported that overexpression of Aurora A protein was found in 19% of CRC samples of various disease stages by immunohistochemistry (IHC) (35). Another group identified Aurora A overexpression by IHC in 48.5% of early-stage CRC samples (23).…”

Selected mutations with high risk of colorectal cancer

“…Niestabilność chromosomalna może promować kancerogenezę zarówno poprzez utratę genów supresorowych nowotworu, jak i zwielokrotnienie liczby kopii onkogenów [26,27]. Przyczyny niestabilności chromosomalnej pozostają wciąż tematem badań, ale prawdopodobnie należą do nich m.in.…”

“…Przyczyny niestabilności chromosomalnej pozostają wciąż tematem badań, ale prawdopodobnie należą do nich m.in. mutacje genów kontroli cyklu komórkowego, takich jak APC czy KRAS [26], dysfunkcja telomerów lub nieprawidłowa liczba i funkcja centrosomów [27].…”

“…Niestabilność mikrosatelitarna (microsatellite instability -MSI) obejmuje zmiany w kodujących i niekodują-cych sekwencjach mikrosatelitarnych w chromosomach, polegające na utracie lub zwielokrotnieniu liczby powtó-rzeń nukleotydów, nadające komórce fenotyp mutatorowy [26,27]. Może być efektem poślizgu polimerazy DNA podczas kopiowania matrycowego DNA lub błędów podczas rekombinacji odcinków DNA [27].…”